The present invention relates to orally-administered pharmaceutical compositions containing interferon-tau and methods of uses thereof.
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Conceptus membranes, or trophectoderm, of various mammals produce biochemical signals that allow for the establishment and maintenance of pregnancy (Bazer, et al., 1983). One such protein, ovine trophoblast protein-one (oTP-1), was identified as a low molecular weight protein secreted by sheep conceptuses between days 10 and 21 of pregnancy (Wilson, et al., 1979; Bazer, et al., 1986). The protein oTP-1 was shown to inhibit uterine secretion of prostaglandin F2-alpha, which causes the corpus luteum on the ovary to undergo physiological and endocrinological demise in nonpregnant sheep (Bazer, et al., 1986). Accordingly, oTP-1 has antiluteolytic biological activity. The primary role of oTP-1 was assumed to be associated with the establishment of pregnancy. oTP-1 was subsequently found to (i) exhibit limited homology (50-70%) with interferon alphas (IFNxcex1) of various species (Imakawa, et al., 1987), and (ii) bind to a Type I interferon receptor (Stewart, et al., 1987). Despite some similarities with IFNxcex1, oTP-1 has several features that distinguish it from IFNxcex1 including the following: oTP-1""s role in reproductive biochemistry (other interferons are not known to have any role in the biochemical regulation of reproductive cycles), oTP-1""s cellular sourcexe2x80x94trophoblast cells (IFNxcex1 is derived from lymphocyte cells), oTP-1""s sizexe2x80x94172 amino acids (IFNxcex1 is typically about 166 amino acids), and oTP-1 is weakly inducible by viruses (IFNxcex1 is highly inducible by viruses). The International Interferon Society recognizes oTP-1 as belonging to an entirely new class of interferons which have been named interferon-tau (IFNxcfx84). The Greek letter xcfx84 stands for trophoblast.
The interferons have been classified into two distinct groups: type I interferons, including IFNxcex1, IFNxcex2, and IFNxcfx89 (also known as IFNxcex1II); and type II interferons, represented by IFNxcex3 (reviewed by DeMaeyer, et al., 1988). In humans, it is estimated that there are at least 17 IFNxcex1 non-allelic genes, at least about 2 or 3 IFNxcex2 non-allelic genes, and a single IFNxcex3 gene.
IFNxcex1""s have been shown to inhibit various types of cellular proliferation. IFNxcex1""s are especially useful against hematologic malignancies such as hairy-cell leukemia (Quesada, et al., 1984). Further, these proteins have also shown activity against multiple myeloma, chronic lymphocytic leukemia, low-grade lymphoma, Kaposi""s sarcoma, chronic myelogenous leukemia, renal-cell carcinoma, urinary bladder tumors and ovarian cancers (Bonnem, et al., 1984; Oldham, 1985). The role of interferons and interferon receptors in the pathogenesis of certain autoimmune and inflammatory diseases has also been investigated (Benoit, et al., 1993).
IFNxcex1""s are also useful against various types of viral infections (Finter, et al., 1991). Alpha interferons have shown activity against human papillomavirus infection, Hepatitis B, and Hepatitis C infections (Finter, et al., 1991; Kashima, et al., 1988; Dusheiko, et al., 1986; Davis, et al., 1989).
In addition, type I interferons are useful in treating autoimmune diseases such as multiple sclerosis (MS). In fact, IFNxcex2 has been tested and approved by the U.S. Food and Drug Administration (FDA) as an MS therapy.
Significantly, however, the usefulness of IFNxcex1""s has been limited by their toxicity: use of interferons in the treatment of cancer, autoimmune disorders and viral disease has resulted in serious side effects, such as fever, chills, anorexia, weight loss, and fatigue (Pontzer, et al., 1991; Oldham, 1985). These side effects often require (i) the interferon dosage to be reduced to levels that limit the effectiveness of treatment, or (ii) the removal of the patient from treatment. Such toxicity has reduced the usefulness of these potent antiviral and antiproliferative proteins in the treatment of debilitating human and animal diseases.
The present invention provides methods of treatment for cancer, autoimmune diseases (such as MS) and for inhibiting cellular proliferation and viral infection. These methods do not have the toxic side effects associated with currently-used therapies, and employ a convenient route of administration.
In one aspect, the present invention includes an improvement in a method of treating a disease condition in a mammal (e.g., mouse, dog or human) responsive to treatment by interferon-tau (IFNxcfx84). The improvement comprises orally administering a therapeutically-effective amount of IFNxcfx84. The orally-administered IFNxcfx84 is preferably ingested by the mammal. In a general embodiment, the IFNxcfx84 is orally-administered at a dosage of between about 1xc3x97105 and about 1xc3x97108 units per day, preferably at a dosage of between about 1xc3x97106 and about 1xc3x97107 units per day. The IFNxcfx84 may be, for example, ovine IFNxcfx84 (OvIFNxcfx84), e.g., a polypeptide having the sequence represented as SEQ ID NO:2, or a human IFNxcfx84 (HuIFNxcfx84), e.g., a polypeptide having the sequence represented as SEQ ID NO:4 or SEQ ID NO:6.
In one embodiment, the disease condition is an immune system disorder, such as an autoimmune disorder (e.g., multiple sclerosis (MS), type I (insulin dependent) diabetes mellitus, lupus erythematosus, amyotrophic lateral sclerosis, Crohn""s disease, rheumatoid arthritis, stomatitis, asthma, allergies or psoriasis). MS is particularly amenable to treatment using the methods of the present invention.
In another embodiment, the disease condition is a cell proliferation disorder, such as a cancer (e.g., hairy cell leukemia, Kaposi""s Sarcoma, chronic myelogenous leukemia, multiple myeloma, superficial bladder cancer, skin cancer (basal cell carcinoma and malignant melanoma), renal cell carcinoma, ovarian cancer, low grade lymphocytic and cutaneous T cell lymphoma, and glioma).
In yet another embodiment, the disease condition is a viral disease (e.g., hepatitis A, hepatitis B, hepatitis C, non-A, non-B, non-C hepatitis, Epstein-Barr viral infection, HIV infection, herpes virus (EB, CML, herpes simplex), papilloma, poxvirus, picorna virus, adeno virus, rhino virus, HTLV I, HTLV II, and human rotavirus).
In another aspect, the invention includes a method of treating an autoimmune disorder in a subject (e.g., a human subject), by orally administering a therapeutically-effective amount of interferon-tau (IFNxcfx84) to the subject. The orally-administered IFNxcfx84 is preferably ingested by the subject. Examples of autoimmune conditions amenable to treatment, dosages, and sources of IFNxcfx84 are as presented above.
The invention also includes a method of decreasing the severity or frequency of a relapse of multiple sclerosis (MS) in a human suffering from MS, by orally administering a therapeutically-effective amount of interferon-tau (IFNxcfx84) to the human. Examples of dosages and sources of IFNxcfx84 are as presented above.
In another aspect, the invention includes a method of treating a cell proliferation disorder in a subject (e.g., a human subject), by orally administering a therapeutically-effective amount of interferon-tau (IFNxcfx84) to the subject. The orally-administered IFNxcfx84 is preferably ingested by the subject. Examples of cell proliferation disorders amenable to treatment, dosages, and sources of IFNxcfx84 are as presented above.
In still another aspect, the invention includes a method of treating a viral disease in a subject (e.g., a human subject), by orally administering a therapeutically-effective amount of interferon-tau (IFNxcfx84) to the subject. The orally-administered IFNxcfx84 is preferably ingested by the subject. Examples of viral diseases amenable to treatment, dosages, and sources of IFNxcfx84 are as presented above.
A further aspect of the invention includes a method of enhancing fertility in a female mammal (e.g., a human female), by orally administering a therapeutically-effective amount of interferon-tau (IFNxcfx84) to the mammal. Examples of dosages and sources of IFNxcfx84 are as presented above.
These and other objects and features of the invention will become more fully apparent when the following detailed description is read in conjunction with the accompanying drawings.